# Role of DNA methylation in regulating striatal molecular rhythm alterations in depression

> **NIH NIH K01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $174,722

## Abstract

PROJECT SUMMARY/ABSTRACT
Major depressive disorder (MDD) is a leading global cause of disability. A prominent feature of MDD is circadian
rhythm disturbances. Recent studies have shown gene expression (GE) rhythms in the human brain using a
“time of death” analysis of postmortem (PM) brain tissue, where GE data is organized across a 24-hour clock
based on individual time of death. Using this approach, it was previously shown that MDD subjects have
disrupted GE rhythms across a number of brain regions, including the striatum. The striatum is composed of the
dorsal striatum and ventral striatum and both have been implicated in stress, anhedonia, and depression. In
preliminary studies, the candidate characterized GE rhythms and phase relationships across the human dorsal
and ventral striatum. The mechanisms driving these rhythmic patterns of GE in the striatum and the alterations
observed in MDD remain to be investigated. This K01 proposal utilizes a multi-omics approach to investigate
DNA methylation (DNAm) as a potential epigenetic mechanism by which GE rhythms are altered in depression.
Given that (1) DNAm in the striatum is strongly implicated in depression and directly influenced by stress and (2)
DNAm rhythms are correlated and time-locked to GE rhythms in the human cortex, the central hypothesis is that
striatal GE rhythm disruptions in depression are driven by chronic-stress induced alterations in DNAm rhythms.
This hypothesis will be tested by the following aims: (1) Determine rhythmic changes in DNAm in the human PM
dorsal and ventral striatum in MDD subjects; (2) Employ a multi-omics data integration approach to determine
how rhythmic changes in DNAm affect transcriptome-wide rhythms in the human PM dorsal and ventral striatum
in MDD subjects; and (3) Determine the regulation of transcriptome-wide rhythms and anhedonia-like behavior
by DNAm in the dorsal and ventral striatum in a mouse model of chronic stress. These studies are central to
understanding the mechanisms underlying circadian disruptions in MDD and may result in the discovery of novel
therapeutic targets for future treatments. To complete the proposed studies and support his career goal of
establishing an independent laboratory to study the epigenetic mechanisms driving circadian rhythm disruptions
in depression, the candidate will require mentored training in: (1) developing conceptual and technical expertise
in the use of rodent models and human PM brain tissue to study the neurobiology of depression; (2) developing
conceptual and technical expertise in the field of epigenetics; and (3) learning advanced biostatistics and
bioinformatics skills to integrate circadian analyses of transcriptomics and epigenomics data. To achieve these
training goals, the candidate has assembled a mentorship team with extensive expertise in the neurobiology of
depression, epigenetics, and biostatistics. The Department of Psychiatry at the University of Pittsburgh offers a
well-funded environment...

## Key facts

- **NIH application ID:** 10487586
- **Project number:** 5K01MH128763-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Kyle Ketchesin
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $174,722
- **Award type:** 5
- **Project period:** 2021-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487586

## Citation

> US National Institutes of Health, RePORTER application 10487586, Role of DNA methylation in regulating striatal molecular rhythm alterations in depression (5K01MH128763-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10487586. Licensed CC0.

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